1. Field of the Invention
The present invention relates to binding proteins, such as monoclonal antibodies, directed to the antigen Matriptase and uses of such binding proteins. More specifically, the present invention relates to fully human, high affinity neutralizing monoclonal antibodies directed to the antigen Matriptase and uses of these antibodies. Aspects of the invention also relate to cell lines expressing such antibodies. The antibodies herein are useful as diagnostics and as treatments for diseases associated with the activity and/or overproduction of Matriptase.
2. Description of the Related Art
Cancer metastasis involves a complex stepwise process involving cell to extracellular matrix communication, tumor cell attachment, spreading, migration, and the dissolution of tissue barriers. Several types of proteases appear to be expressed at elevated levels during cancer progression. The protease Matriptase is thought to be involved in the degradation of extracellular matrix (ECM) and in tissue remodeling, both of which are components of cancer progression and metastasis processes. Matriptase is also known as “MT-SP1” and Tumor-Associated differentially expressed Gene-15.
Matriptase is a transmembrane protein with a trypsin-like, extracellular serine protease domain. Human Matriptase (SEQ ID NO: 1) was initially isolated from human breast cancer cells. The Matriptase protein contains two tandem complement subcomponent “CUB” repeats (Complement factor/1R-urchin embryonic growth factor/bone morphogenic protein) and four tandem repeats of the low density lipoprotein receptor class “A” domain (“LDL”; Lin et al., J. Biol. Chem. 274: 18231-6 (1999)).
Matriptase primarily cleaves target proteins at arginine and lysine residues, similar to the majority of serine proteases, including trypsin and plasmin. Matriptase exhibits broad spectrum substrate cleavage activity which may contribute to its gelatinolytic activity. Several cancer-related proteins have been shown to be cleaved and activated by Matriptase. Among these are the protease activated receptor-2, urokinase-type plasminogen activator (Toshihiko et al., 2000, Journal of Biological Chemistry, 275:26333-26342); and hepatocyte growth factor (Lee et al., (2000), Journal of Biological Chemistry, 275:36720-36725).
The finding that Matriptase is involved in cancer progression has led researchers to investigate molecules that inhibit Matriptase activity. For example, U.S. Pat. No. 6,677,377 discusses small molecules which inhibit Matriptase, and their use in treating carcinoma progression. However, small molecule inhibitors can be non-specific for enzymes other than Matriptase, and may lead to undesirable toxicity following treatment.
Antibodies to Matriptase (MT-SP1) were discussed in Sun et al., 2003, Biochemistry 42: 892-900, and Lin et al., 1997, Journal of Biological Chemistry, 272: 9147-9152. However, because these antibodies were generated using phage display technology, they are potentially immunogenic in humans.